Fatality in cancer is generally due to metastasis and development of resistance to chemotherapy (Fisher, 1994; Liotta et al., 1991). Metastasis and resistance to chemotherapy are mostly due to overexpression of pro-metastatic, pro-angiogenic, multi-drug resistance and anti-apoptotic genes (Baldini, 1997; Fisher, 1994; Wang et al., 1999a). The expression of a significant number of these genes is regulated by NF-κB, Activator Protein (AP-1) and the Ets family of transcription factors (Baeuerle & Henkel, 1994; Grumont et al., 1999; Gutman & Wasylyk, 1990; Lee et al., 1999; Wang et al., 1999b; Wang et al., 1998; Zong et al., 1999).
Expression of the pro-metastatic genes interleukin-6 (IL-6), urokinase plasminogen activator, matrix metalloproteinase 9, the pro-angiogenic gene IL-8 and the anti-apoptotic genes c-IAP1, cIAP2, TRAF1, TRAF2, Bfl-1/A1, Bcl-XL, and Mn-SOD is induced by NF-κB (Baeuerle & Henkel, 1994; Grumont et al., 1999; Jones et al., 1997; Lee et al., 1999; Wang et al., 1999b, Wang et al., 1998; Zong et al., 1999). Normally, NF-κB resides in the cytoplasm in an inactive state bound to IκB proteins (Baeuerle & Henkel, 1994). When cells are exposed to TNFα, IL-1 or chemotherapeutic agents, a multisubunit IκB kinase complex (IKC) is activated, which phosphorylates IκBs (Zandi & Karin, 1999). NF-κB dissociates from phosphorylated IκBs, translocates to the nucleus and activates target genes (Baeuerle & Henkel, 1994). The ability of activated NF-κB to induce gene expression depends on the cell type and the type of NF-κB inducer.
For example, in cell types that are sensitive to TNFα and chemotherapy-induced apoptosis, NF-κB is inactivated by caspases and the induction of NF-κB-dependent cell survival signals is markedly reduced (Levkau et al., 1999). In contrast, activation of NF-κB by growth factors or IL-1 can cause an increase in anti-apoptotic gene expression and subsequent resistance to TNF and chemotherapy (Wang et al., 1996). Inhibition of NF-κB activation by IκB overexpression can convert TNF- and chemotherapy-resistant cells to a sensitive phenotype (Beg & Baltimore, 1996; Van Antwerp et al., 1996; Wang et al., 1996).
Recent studies indicate that NF-κB is constitutively active in a number of tumors including Hodgkin's lymphoma, melanoma, juvenile myelomonocytic leukemia, cutaneous T cell lymphoma, melanoma, squamous cell carcinoma and Bcr-Abl-induced transformation (Bargou et al., 1997; Dong et al., 1999; Giri & Aggarwal, 1998; Reuther et al., 1998; Shattuck-Brandt & Richmond, 1997). Constitutive NF-κB activation has been described in a subset of breast cancers (Cogswell et al., 2000; Nakshatri et al., 1997; Sovak et al., 1997).
Although a number of drugs, including aspirin, have been described as having some ability to prevent NF-κB activation (Yin et al., 1998), a need exists for compounds that can potently inhibit NF-κB activation at clinically achievable doses. Such drugs can be used as primary or adjunct therapeutic agents in the treatment of cancer, or in other pathologies involving NF-κB activation.